2026-04-29T04:00:29Zhttps://repisalud.isciii.es/rest/oai/request

oai:repisalud.isciii.es:20.500.12105/131762024-09-27T10:10:38Zcom_20.500.12105_19604com_20.500.12105_2051col_20.500.12105_19607

00925njm 22002777a 4500 dc Cagin, Umut author Puzzo, Francesco author Gomez, Manuel J author Moya-Nilges, Maryse author Sellier, Pauline author Abad, Catalina author van Wittenberghe, Laetitia author Daniele, Nathalie author Guerchet, Nicolas author Gjata, Bernard author Collaud, Fanny author Charles, Severine author Sola, Marcelo Simon author Boyer, Olivier author Krijnse-Locker, Jacomina author Ronzitti, Giuseppe author Colella, Pasqualina author Mingozzi, Federico author 2020-09 Pompe disease is a neuromuscular disorder caused by disease-associated variants in the gene encoding for the lysosomal enzyme acid α-glucosidase (GAA), which converts lysosomal glycogen to glucose. We previously reported full rescue of Pompe disease in symptomatic 4-month-old Gaa knockout (Gaa-/-) mice by adeno-associated virus (AAV) vector-mediated liver gene transfer of an engineered secretable form of GAA (secGAA). Here, we showed that hepatic expression of secGAA rescues the phenotype of 4-month-old Gaa-/- mice at vector doses at which the native form of GAA has little to no therapeutic effect. Based on these results, we then treated severely affected 9-month-old Gaa-/- mice with an AAV vector expressing secGAA and followed the animals for 9 months thereafter. AAV-treated Gaa-/- mice showed complete reversal of the Pompe phenotype, with rescue of glycogen accumulation in most tissues, including the central nervous system, and normalization of muscle strength. Transcriptomic profiling of skeletal muscle showed rescue of most altered pathways, including those involved in mitochondrial defects, a finding supported by structural and biochemical analyses, which also showed restoration of lysosomal function. Together, these results provide insight into the reversibility of advanced Pompe disease in the Gaa-/- mouse model via liver gene transfer of secGAA. Mol Ther. 2020; 28(9):2056-2072 1525-0024 http://hdl.handle.net/20.500.12105/13176 32526204 10.1016/j.ymthe.2020.05.025 Molecular therapy : the journal of the American Society of Gene Therapy Rescue of Advanced Pompe Disease in Mice with Hepatic Expression of Secretable Acid α-Glucosidase.